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Spinal cord phosphoproteome of SCA2/ALS13 mouse model

ABSTRACT: Toxic polyglutamine (polyQ) expansions in ATXN2 trigger neurodegenerative processes, causing Spinocerebellar Ataxia type 2 (SCA2), and enhancing TDP 43-dependent pathology in Amyotrophic Lateral Sclerosis (ALS) / Fronto-Temporal Dementia (FTD). Primary disease events can be compensated transiently, delaying disease manifestation. To define potential therapy targets, we documented how cells modify their phospho-signals and how the ATXN2 interactome changes, using preferentially affected nervous tissues from end-stage Atxn2-CAG100-KnockIn mice.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Spinal Cord

SUBMITTER: Jana Key

LAB HEAD: Georg Auburger

PROVIDER: PXD062823 | Pride | 2025-09-29

REPOSITORIES: Pride

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			Action	DRS
	20210303_Swissprot_Mouse_ISO4prot.fasta	Fasta
	210308_32716_KA_L-017.raw	Raw
	210308_32717_KA_L-009.raw	Raw
	210308_32718_KA_L-008.raw	Raw
	210308_32719_KA_L-011.raw	Raw

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Publications

Spinal cord phosphoproteome of SCA2 mouse model reveals alteration of ATXN2-N-term PRM-SH3-actin interactome and of autophagy.

Almaguer-Mederos Luis-Enrique LE Kandi Arvind Reddy AR Sen Nesli-Ece NE Canet-Pons Júlia J Berger Luca-Malena LM Stokes Matthew P MP Abell Kathryn K Key Jana J Gispert Suzana S Auburger Georg G

Molecular & cellular proteomics : MCP 20250922

Toxic polyglutamine (polyQ) expansions in ATXN2 trigger neurodegenerative processes, causing Spinocerebellar Ataxia type 2 (SCA2), and enhancing TDP-43-dependent pathology in Amyotrophic Lateral Sclerosis (ALS) / Fronto-Temporal Dementia (FTD). Primary disease events can be compensated transiently, delaying disease manifestation. To define potential therapy targets, here we studied how cells modify phosphoprotein signals, using preferentially affected nervous tissue from end-stage Atxn2-CAG100-K ...[more]

PMID: 40992657

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Inhibition of spinal cord Hsp90 enhances morphine anti-nociception by activating an ERK/RSK pathway

Project description:Morphine and other opioids continue to be commonly utilized as clinical analgesics, despite their numerous adverse side effects, including respiratory depression, addiction, and tolerance. The modulation of µ-opioid receptor (MOR) signaling and subsequent behavioral output is one viable approach to improve opioid therapy. Heat shock protein 90 (Hsp90) is a molecular chaperone protein that has recently been implicated in downstream MOR signaling within the brain in mice. Here we identify a context-dependent impact on MOR signaling in which the inhibition of Hsp90 within the spinal cord promotes morphine induced anti-nociception. We show that intrathecal and not systemic administration of the Hsp90 inhibitors 17-AAG or KU-32 amplifies morphine-induced anti-nociception in both thermal and mechanical pain models. Further, we demonstrate that the inhibition of Hsp90 allows for ERK phosphorylation after opioid treatment. ERK activation was localized within the dorsal horns of the spinal cord, which are heavily populated with primary afferents responsible for nociception. The behavioral effects observed with Hsp90 inhibitors were abolished upon intrathecal U0126 (ERK inhibitor) and cycloheximide (translation inhibitor) treatment, suggesting that downstream ERK phosphorylation and rapid protein translation are responsible for the observed amplification of anti-nociception. Quantitative proteomic analysis identified upregulated RSK with spinal cord Hsp90 inhibition, which we further found was necessary for the observed enhancement of anti-nociception. Taken together, we have uncovered a novel downstream MOR ERK/RSK cascade, localized to the spinal cord and repressed by Hsp90, whose modulation may allow for enhanced efficacy and decreased side effects during opioid therapy.

2020-04-24 | PXD015060 | Pride

Quantitative proteomic analysis of cellular nuclear protein TMT markers from rat spinal cord tissue samples in neuropathic pain model

Project description:To further reveal the mechanism of neuropathic pain, we simulated neuropathic pain by constructing a chronic constriction injury of the sciatic nerve (CCI) model, followed by quantitative proteomic analysis of rat spinal cord cell nuclei at 1 day, 7 days and sham-operated groups after CCI. A total of 3 samples from each group were used. A total of 5039 proteins were identified in this study, of which 4469 proteins contained quantitative information. Differential proteins were defined by a threshold of change >1.3-fold and t-test p-value <0.05.v

2023-01-17 | PXD034960 | Pride

Proteomic analysis of the spatiotemporal based molecular kinetics of acute spinal cord injury identifies a time- and segment-specific window for effective tissue repair.

Project description:Spinal cord injury (SCI) represents a major debilitating health issue with a direct socioeconomic burden on the public and private sectors worldwide. Although several studies have been conducted to identify the molecular progression of injury sequel due from the lesion site, still the exact underlying mechanisms and pathways of injury development have not been fully elucidated. In this work, based on OMICs, 3D MALDI imaging, cytokines arrays, confocal imaging we established for the first time that molecular and cellular processes occurring after spinal cord injury (SCI) are altered between the lesion proximity, i.e., rostral and caudal segments nearby the lesion (R1-C1) whereas segments distant from R1-C1, i.e., R2-C2 and R3-C3 levels co-expressed factors implicated in neurogenesis. Delay in T regulators recruitment between R1 and C1 favor discrepancies between the two segments. This is also reinforced by presence of neurites outgrowth inhibitors in C1, absent in R1. Moreover, the presence of immunoglobulins (IgGs) in neurons at the lesion site at 3 days, validated by mass spectrometry, may present additional factor that contributes to limited regeneration. Treatment in vivo with anti-CD20 one hour after SCI did not improve locomotor function and IgG expression. These results open the door of a novel view of the SCI treatment by considering the C1 as the therapeutic target.

2016-06-08 | PXD003375 | Pride

Aquaporin-4 mRNA binding proteins

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2021-05-27 | PXD024792 | Pride

Mps1 regulates kinetochore-microtubule attachment stability via the Ska complex to ensure error-free chromosome segregation

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2018-10-24 | PXD006135 | Pride

Danio spinal cord injury

Project description:Adult zebrafish have the ability to recover from spinal cord injury and exhibit re-growth of descending axons from the brainstem to the spinal cord. We performed gene expression analysis using microarray to find damage-induced genes after spinal cord injury, which shows that Sox11b mRNA is up-regulated at 11 days after injury. However, the functional relevance of Sox11b for regeneration is not known. Here, we report that the up-regulation of Sox11b mRNA after spinal cord injury is mainly localized in ependymal cells lining the central canal and in newly differentiating neuronal precursors or immature neurons. Using an in vivo morpholino-based gene knockout approach, we demonstrate that Sox11b is essential for locomotor recovery after spinal cord injury. In the injured spinal cord, expression of the neural stem cell associated gene, Nestin, and the proneural gene Ascl1a (Mash1a), which are involved in the self-renewal and cell fate specification of endogenous neural stem cells, respectively, is regulated by Sox11b. Our data indicate that Sox11b promotes neuronal determination of endogenous stem cells and regenerative neurogenesis after spinal cord injury in the adult zebrafish. Enhancing Sox11b expression to promote proliferation and neurogenic determination of endogenous neural stem cells after injury may be a promising strategy in restorative therapy after spinal cord injury in mammals. Spinal cord injury or control sham injury was performed on adult zebrafish. After 4, 12, or 264 hrs, a 5 mm segment of spinal cord was dissected and processed (as a pool from 5 animals) in three replicate groups for each time point and treatment.

2010-10-19 | E-GEOD-20460 | biostudies-arrayexpress

Quantitative proteomics after spinal cord injury in a regenerative and a non-regenerative stage in Xenopus laevis

Project description:The capacity to regenerate the spinal cord after an injury is a coveted trait that only a limited group of non-mammalian organisms can achieve. In Xenopus laevis, this capacity is only present during larval or tadpole stages, but is absent during postmetamorphic frog stages. This provides an excellent model for comparative studies between a regenerative and a non-regenerative stage to identify the cellular and molecular mechanisms that explain the difference in regenerative potential. Here, we used iTRAQ chemistry to obtain a quantitative proteome of the spinal cord 1 day after a transection injury, and used sham operated animals as controls. We quantified a total of 6,384 proteins, with 172 showing significant differential expression in the regenerative stage and 240 in the non-regenerative stage, with an overlap of only 14 proteins. Functional enrichment analysis revealed that while the regenerative stage downregulated synapse/vesicle and mitochondrial proteins, the non-regenerative stage upregulated lipid metabolism proteins, and downregulated ribosomal and translation control proteins. Furthermore, STRING network analysis showed that proteins belonging to these groups are highly interconnected, providing interesting candidates for future functional studies.

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Mass spectrometry data supporting "Mass spectrometry imaging of SOD1 protein-metal complexes in SOD1G93A transgenic mice implicates demetalation with pathology"

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Protein variability in cerebrospinal fluid and its possible implications for neurological protein biomarker research

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ALK fusion NSCLC oncogenes promote survival and inhibit NK cell responses via SERPINB4 expression

Project description:Anaplastic lymphoma kinase (ALK) fusion variants in non-small-cell-lung cancer (NSCLC) consist of numerous dimerising fusion partners, with the most common being EML4. Clinical data suggests that the degree of treatment benefit in response to ALK tyrosine kinase inhibitors (TKIs) differs among the variant present in the patient tumor. Therefore, a better understanding the oncogenic signaling networks driven by different ALK-fusion variants is important. Here, we developed highly controlled doxycycline-inducible cell models bearing four different ALK fusion proteins, namely EML4-ALK-V1, EML4-ALK-V3, KIF5B-ALK, and TFG-ALK, in the context of non-tumorigenic NL20 human bronchial epithelial cells. These were complimented by patient-derived NSCLC cell lines harboring either EML4-ALK-V1 or EML4-ALK-V3 fusions. RNAseq and phosphoproteomics analysis were employed to identify dysregulated genes and hyper/hypo-phosphorylated proteins associated with ALK fusion expression. Among ALK fusion induced responses, we noted a robust inflammatory signature that included up-regulation of the Serpin B4 serine protease inhibitor in both NL20-inducible cell models and ALK-positive NSCLC patient-derived cell lines. We show that STAT3 is a major transcriptional regulator of SERPINB4 downstream of ALK fusions, along with NF-B and AP1. The upregulation of SERPINB4 promotes survival of ALK fusion expressing cells and inhibits natural killer (NK) cell-mediated cytotoxicity. In conclusion, our study reveals a novel ALK downstream survival axis that regulates Serpin B4 expression and identifies a molecular target that has potential for therapeutic impact targeting the immune response together with ALK TKIs in NSCLC.

2023-02-16 | PXD035100 | Pride

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